The Story of Group 5 Pulmonary Hypertension
Pulmonary hypertension (PH) has historically been categorized into 5 groups based on similar pathophysiological mechanisms, hemodynamic characteristics, and therapeutic management. Group 5 has evolved over time in concert with our understanding of PH. Currently, it is comprised of diseases leading to PH with unclear and/or multifactorial mechanisms. We will review the historical context of the classification system and how group 5 has morphed into its current classification. We will briefly review the diseases encompassed in group 5 and the current understanding of the associated pathophysiological mechanism leading to PH. We provide a brief review of the diseases of group 5 PH, including the proposed mechanism for PH and potential therapies. Group 5 is comprised of a varied group of diseases, and the mechanisms leading to PH in this group are complex, multifactorial, and often incompletely understood.
INTRODUCTION
The clinical classification system for pulmonary hypertension (PH) allows for the categorization of associated diseases with similar pathophysiological mechanisms, hemodynamic characteristics, and therapeutic management. However, classification systems are limited by the completeness of our understanding and the confines of our system. Group 5 allows for these limitations by grouping the heterogenous diagnoses which lack a clear and predominant pathophysiological mechanism for the development of PH. Included in this group are (1) hematologic disorders: chronic hemolytic anemia, including sickle cell disease and β-thalassemia, and myeloproliferative disease; (2) systemic and metabolic disorders: Gaucher disease, glycogen storage disease, neurofibromatosis, sarcoidosis, and pulmonary Langerhans cell histiocytosis (PLCH); (3) others: chronic renal failure and fibrosing mediastinitis; and (4) complex congenital heart disease.1 We will review the history of the PH classification system and then briefly review the components of group 5.
HISTORY OF THE PH CLASSIFICATION SYSTEM
Pulmonary arterial sclerosis was first described in 1891. It was not until 1951, in concert with the development of right heart catheterization (RHC), that hemodynamic variation was noted and an elevation in pulmonary pressures was coined “primary PH.” Soon after, the concepts of vasoreactive PH and PH due to overflow of the pulmonary circulation from congenital heart disease were described.2 In 1973, the World Health Organization met in Geneva to discuss PH for the first time. After this meeting, PH was subsequently classified into primary PH or secondary PH depending on the presence of an attributable cause.3
In 1981, a National Institutes of Health-funded national registry for PH began and allowed for the recognition of groups of patients with similar hemodynamic characteristics, survival, demographics, and associated diseases.4 The Second World Health Symposium for PH was not held until 1998, where the first clinical classification system the Evian classification was proposed. Based on data from the PH registry, categories were developed which shared similarities in pathophysiological mechanisms, clinical presentation, and therapeutic options. The Evian classification system divided PH patients into 5 familiar categories with group 5 consisting of disorders directly affecting the pulmonary vasculature (Table 1). Group 5 was then subdivided into (1) inflammatory disorders including schistosomiasis and sarcoidosis and (2) mechanical obstruction including pulmonary capillary hemangiomatosis. After the Second Symposium, multiple case series were published indicating new risk factors for PH. For instance, splenectomy was found to be associated with PH as well as certain hemoglobinopathies and metabolic disorders. The Third World Symposium on PH in 2003 evaluated and revised the proposed Evian classification scheme incorporating newly associated diagnoses. One of the most notable revisions reclassified pulmonary capillary hemangiomatosis into group 1 with pulmonary veno-occlusive disease due to similar histological changes and clinical risk factors as group 1 PAH, despite primarily affecting the capillary and venous system. Group 5 was subsequently termed, “miscellaneous,” and included sarcoidosis, histiocytosis X, lymphangiomatosis, and compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis).5 Over the years, the diseases which occurred concurrently with PH continued to expand. At the Fourth World Symposium, the Dana Point classification scheme allowed for further delineation of group 5. Often due to the rarity of these diseases causing PH, this group provided more of a diagnostic differential when more common causes of PH had been ruled out. Group 5 became subdivided into hematologic disorders, systemic disorders, metabolic disorders, mechanical obstruction, and chronic renal failure.6 The most recent updates to the clinical classification scheme occurred in 2018 at the Sixth World Symposium (Table 2).1 Complex congenital heart disease such as segmental disorders, single ventricle physiology, and scimitar syndrome were added to group 5, as these anomalies are increasingly difficult to define and classify.7
Over the last 20 years, group 5 has undergone notable changes. From initially being a group of diseases directly affecting the pulmonary vasculature, it has morphed into the current category where the difficulty in classifying the mechanism of disease is the unifying element. Many of the diseases in group 5 are rare, or PH is an uncommon manifestation of the disease. This in part contributes to group 5 being a less studied, often overlooked, and underrecognized group. By its very nature, diseases in group 5 may need to be reclassified. The evolution of group 5 mirrors our progressive understanding of PH and its associated diseases.1
BRIEF REVIEW OF GROUP 5: PH WITH UNCLEAR AND/OR MULTIFACTORIAL MECHANISMS
In general, PH is due to increased pulmonary vascular resistance to flow, increased cardiac output, and/or increased postcapillary pressure. Group 5 encompasses disorders that cause PH through all of these pathways or those in which understanding for the pathway is incomplete.1,8
5.1 Hematologic Disorders
Chronic Hemolytic Anemia: The association of PH with chronic hemolytic anemia is both incompletely understood and multifactorial. Sickle cell disease is complicated by PH in approximately 10% of patients through multiple mechanisms and is associated with increased mortality. Interestingly, echocardiogram has been found to significantly overestimate the prevalence of PH in this cohort, and RHC is paramount in diagnosing these patients. The hemodynamic profile is also unique and characterized by increased cardiac output and relatively low pulmonary vascular resistance. Among patients found to have PH by RHC, both precapillary and postcapillary PH are present. Proposed mechanisms include an increase in cardiac output in the setting of anemia, increased resistance due to thromboembolic disease, altered blood viscosity, nitric oxide and arginine depletion due to free plasma hemoglobin scavenging and the effects on endothelial production of nitric oxide, chronic inflammation, injury from acute chest syndrome, and lastly, an increase in postcapillary pressure due to restrictive cardiomyopathy.1,9
There is limited data on the association of α-thalassemia and PH. Severe forms of α-thalassemia, specifically when there are 3 alleles affected, are associated with PH. β-thalassemia intermedia and major are also associated with PH. In patients with β-thalassemia intermedia, 1 gene is affected, and transfusions are often not required. PH in these patients is thought to be due to chronic lowgrade hemolysis and the subsequent depletion of nitric oxide and arginine. In patients with β-thalassemia major, there are 2 defective genes, leading to more severe anemia, and these patients are often transfusion dependent. Iron overload, from chronic transfusions, plays a role in PH in β-thalassemia major by causing oxidative stress and endothelial dysfunction. Additionally, iron accumulation in cardiac tissues can lead to both right and left cardiac dysfunction. Iron overload in the lung can additionally lead to excess hemosiderin deposits resulting in fibrosis and arterial stiffening. Splenectomy increases the risk of PH in both forms of β-thalassemia.10–12
Other less common hemolytic processes linked to PH include hereditary spherocytosis, microangiopathic hemolytic anemia, and paroxysmal nocturnal hemoglobinuria.12
Myeloproliferative Disorders: Chronic myeloproliferative disorder (CMPD) describes a group of diseases where a multipotent hematopoietic progenitor cell overproduces a type of blood cell without significant dysplasia. The prevalence of PH in patients with CMPD is unknown.8,13
CMPD is associated with both precapillary and postcapillary pathology. Precapillary causes of PH in CMPD include portal hypertension secondary to myeloid metaplasia as a complication of myelofibrosis and dasatinib, a tyrosine kinase inhibitor and frequently used treatment for chronic myeloid leukemia. Tumor microembolism can occur in CMPD related to translocation of megakaryocytes. Megakaryocytes and myeloid progenitor cells are larger than the alveolar capillary diameter and can occlude these vessels leading to obstruction and secondary microthrombosis.13,14 It has been proposed that cytoreductive therapy may have a role in treatment of precapillary PH in patients with CMPD. Additionally, there appears to be a relationship between elevated pulmonary artery pressures and elevated platelet counts in myeloid metaplasia and essential thrombocytosis. Elevated platelet-derived growth factor released from activated platelets stimulates smooth muscle hyperplasia and is one suggested causal mechanism. Additionally, elevated hemoglobin in polycythemia vera has been associated with PH though not fully established. Last, pulmonary veno-occlusive disease can occur and can be secondary to CMPD or secondary to treatment of the CMPD with cytotoxic chemotherapy and hematopoietic stem cell transplant.13
In addition to pulmonary arterial pathology in patients with CPMD, patients also demonstrate findings consistent with chronic thromboembolic PH (CTEPH). CTEPH is most often linked to polycythemia vera and essential thrombocytosis. Both diseases can lead to a thrombophilic state. In polycythemia vera, the elevated hemoglobin levels lead to hyperviscosity and disturbances in blood flow increasing platelet activation. Blood cell aggregates in both polycythemia vera and essential thrombocytosis can induce platelet activation and thrombosis in small vessels. Additionally, spontaneous erythropoietin-independent erythroid colony formation as seen in polycythemia vera, particularly in the hepatic veins, increases thrombotic risk. Unlike the association with elevated platelet counts and PH in precapillary disease from essential thrombocytosis, the degree of thrombocytosis has not been found to be associated with risk for thrombosis in CTEPH.13
5.2. Systemic and Metabolic Disorders
PLCH: PLCH is a rare smoking-related interstitial lung disease predominantly affecting young adults (Figure 1). PH is a known complication of PLCH and tends to occur in more severe disease. The mechanism is incompletely understood and appears multifactorial. Based on histologic evidence both pulmonary arterial remodeling and postcapillary involvement are noted. A decline in the diffusing capacity of the lungs for carbon monoxide can be indicative of the development of PH in these patients. Vasodilator therapies may improve World Health Organization functional class in this population. However, due to the histologic evidence of venule involvement in those with PH associated with PLCH, there is a potential risk for pulmonary edema related to vasodilator therapy, and their use should be approached with caution. Ultimately, patients may benefit from lung transplantation. 15,16
Citation: Advances in Pulmonary Hypertension 20, 2; 10.21693/1933-088X-20.2.40
Gaucher Disease: Gaucher disease is an inherited lysosomal storage disease caused by a defect in the gene encoding β-glucocerebrosidase. Lack of functional β-glucocerebrosidase leads to an accumulation of lipid in reticuloendothelial cells. These lipid-laden cells are predominantly macrophages and accumulate in the liver, spleen, bone marrow, brain, and lungs. Additionally, these lipid-laden cells activate macrophages leading to the release of cytokines and lysosomal proteins. Three major forms of Gaucher disease have been described. Type 1 is associated with PH.17 The exact mechanism is unclear, though splenectomy, female sex, family history of Gaucher disease complicated by PH, and lack of treatment with enzyme replacement therapy are risk factors. Fortunately, enzyme replacement therapy has effectively reduced the need for splenectomy in these patients with an expectant decline in associated PH. One case series reported favorable outcomes in patients with Gaucher disease complicated by PH who were treated with enzyme replacement and occasionally pulmonary vasodilators.18
Glycogen Storage Disease: Glycogen storage disorders are characterized by abnormal glycogen deposit due to deficiencies in enzymes responsible for the storage or breakdown of glycogen. This leads to hypoglycemia, hyperlipidemia, hepatomegaly, myopathy, and growth retardation. The type of glycogen storage disorder is associated with the particular enzyme deficiency.8 While PH has been reported in multiple types of glycogen storage disorders, it is most commonly associated with type 1a.8.19,20 A clear causal mechanism has not been established. Pathology indicates plexiform lesions, intimal fibrosis, and medial hypertrophy consistent with precapillary PH. An increase in serotonin levels in these patients has also been described and thought to play some role in the causal pathway.19,20
Neurofibromatosis: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder leading to the loss of neurofibromin. Neurofibromin has a known role in tumor suppression, and without it, there is constitutive activation and deregulation of pathways involved in cell proliferation and differentiation. The classic skin findings include café au lait spots, axillary and inguinal freckling, and dermal neurofibromas. These patients are predisposed to tumors, malignancy, learning disabilities, epilepsy, and less commonly, interstitial lung disease. Cardiac abnormalities include atrial septal defects, ventricular septal defect, mitral and aortic insufficiency, hypertrophic cardiomyopathy, and intracardiac tumors. Vascular lesions are severe though less common and cause renovascular hypertension, myocardial infarction, cerebral infarction, and ischemic bowel disease. PH is a rare but severe complication of NF1.21
Diagnosis of PH typically occurs late in the course of NF1 (50–65 years old) despite full penetrance by age 5 and in contrast to other heritable forms of pulmonary arterial hypertension (PAH). Like many forms of PAH, it has a female predominance. Unfortunately, based on case reports, it appears PAH-specific treatments have limited benefit in the population. In part, this may be related to the limited information on this disease process, as well as multiple causal pathways for PH in this population beyond pulmonary arterial remodeling including lung parenchymal disease, skeletal deformities leading to restrictive lung disease, left heart disease, as well as reports of pulmonary capillary hemangiomatosis and pulmonary veno-occlusive disease. Because of this and the high associated mortality after diagnosis, early referral for lung transplant assessment is recommended. The decision to pursue transplant must be coupled with the understanding that immunosuppressive therapy required posttransplant will increase the risk of cancer for these patients.21
Sarcoidosis: Sarcoidosis is a multisystem granulomatous disease which is thought to develop due to the interplay of extrinsic antigen exposure, human leukocyte antigen (HLA) class 2 molecules, and T-cell receptors. Genetic susceptibility may relate to carriage of particular HLA genes. Because there are no specific findings unique to sarcoidosis, it is a diagnosis of exclusion. Lung involvement is present in more than 90% of diagnosed patients, though presentations are variable and include restrictive disease, airflow obstruction, thoracic adenopathy, and parenchymal disease.22 Consistent with the variable presentation of sarcoidosis, PH in patients with sarcoid can be a consequence of a variety of factors including parenchymal lung disease, extrinsic compression of pulmonary vessels from adenopathy, direct myocardial involvement, granulomatous arteriopathy, pulmonary veno-occlusive disease, and portopulmonary hypertension. Because of this, sarcoidosis is classified as group 5 despite characteristics consistent with group 3.1 The diagnosis of sarcoid-associated PH increases morbidity and mortality. The utility of vasodilator therapy is unclear and, because of the multifactorial nature of disease, likely varies based on the patient’s particular phenotype.8,23
5.3 Others
Chronic Renal Failure: Patients with chronic kidney disease (CKD) and with end-stage kidney disease maintained on long-term hemodialysis have an increased propensity to develop PH. Additionally, in this population, PH is an independent predictor of mortality. The underlying mechanisms to develop PH are multiple, though postcapillary PH is the predominant phenotype. Patients can have increased postcapillary pressure in the setting of left heart disease and volume overload.24,25 Large arteriovenous fistulas, particularly with shunt flow greater than 2 L/min, can also lead to elevated pulmonary pressures in the setting of high cardiac output and excess pulmonary arterial flow.25 Concomitant renal anemia can contribute to high output states. Lastly, precapillary PH may be present in dialysis patients, particularly with chronic uremia, due to impaired endothelial function, decreased bioavailability of nitric oxide, and increased levels of endothelin.8,24 One prospective trial found that precapillary PH was only found in patients undergoing dialysis, as opposed to those with CKD not requiring renal replacement therapy. They also found an elevated transpulmonary gradient (>12–15 mmHg) signified a precapillary component regardless of volume status.24
Management of patients with PH in the setting of CKD with or without dialysis largely depends on the driving mechanism. Optimizing volume status with dialysis or diuretics, adequate iron and erythropoietin supplementation, maintaining acceptable calcium-phosphate levels, as well as shunt revisions in patients with high flows through their arteriovenous fistulas are all potentially useful interventions in this population to decrease pulmonary pressures.8,24,25
Fibrosing Mediastinitis: Fibrosing mediastinitis is a rare disease resulting from progressive fibrosis leading to compression of mediastinal structures. In North America, fibrosing mediastinitis is most associated with pulmonary histoplasmosis but can complicate several granulomatous diseases including sarcoidosis and tuberculosis. It has also been reported with several fungal infections including aspergillosis, blastomycosis, mucormycosis, cryptococcosis, coccidioidomycosis, and infection with Wuchereria bancrofti. Lastly, autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, Behçet disease, mediastinal radiation, and silicosis, and specific drugs have been implicated in the development of fibrosing mediastinitis.26–29 Fibrotic compression of the pulmonary artery and veins can lead to PH (Figure 2). Most patients demonstrate precapillary PH, though occasionally postcapillary PH is described likely due to significant occlusion of pulmonary veins. Depending on the area of involvement, pulmonary artery stenting is a potential treatment, though duration of benefit may be limited by stent stenosis.28 Targeted PAH therapies have been attempted, but data are limited to case reports, and in some cases, vasodilators can lead to worsening oxygenation if lung parenchymal involvement or pulmonary venous involvement is extensive.29 In patients with fibrosing mediastinitis due to histoplasmosis, biopsy demonstrated accumulation of CD20-positive B lymphocytes.30 Subsequently, 1 case series used rituximab in 3 patients with fibrosing mediastinitis due to histoplasmosis with reduction in lesion size and metabolic activity.31
Citation: Advances in Pulmonary Hypertension 20, 2; 10.21693/1933-088X-20.2.40
5.4 Complex Congenital Heart Disease
The last category in group 5 is complex congenital heart disease. This group is divided into patients with segmental PH, single ventricle physiology, and scimitar syndrome. Segmental PH includes those with differential blood flow through the pulmonary circulation due to an isolated pulmonary artery of ductal origin, an absent pulmonary artery, pulmonary atresia, or hemitruncus. Single ventricle patients are included regardless of operable status. These patients are unique given variable blood flow depending on their age, completion of Blalock-Taussig Shunt, Glenn procedure, or Fontan procedure. Additionally, the chronic nonpulsatile pulmonary circulation induces a form of PH that is dissimilar to other diseases associated with PH and may develop despite a relatively low mean pulmonary artery pressure.7 Scimitar syndrome is a rare congenital cardiovascular defect with partial anomalous pulmonary venous connection. Typically, this occurs on the right, and these pulmonary veins drain into the inferior vena cava. The right lung is frequently hypoplastic and receives its blood supply from systemic arteries.32 At this point, there is insufficient data showing that targeted therapies are safe and efficient in this population.7
CONCLUSIONS
Group 5 is an evolving, complex, and varied group of disorders causing PH. In general, this group is less well understood and varies from rare diseases to relatively common diseases such as CKD. Ongoing investigation into the mechanism of disease for group 5 will further unlock the intricacies of PH. Because of the multifactorial mechanisms that cause PH in this group, treatment modalities for these patients are varied and at times lacking. However, in all underlying diseases, PH often worsens morbidity and mortality and is important to evaluate and optimize. In general, pulmonary vasodilators are of limited utility in this group and should be used cautiously by providers with experience in both the mechanism of disease and pulmonary vasodilators.
33-year-old female with pulmonary Langerhans cell histiocytosis by biopsy complicated by severe pulmonary hypertension. Computed tomography images with thin-walled, irregular cysts, architectural distortion of the lungs, and small nodules. Initiated on sildenafil, macitentan, and intravenous trepositinil with improvement in pro B-type natriuretic peptide and 6-minute walk. Referred for lung transplant evaluation.
78-year-old male with fibrosing mediastinitis complicated by pulmonary hypertension. Computed tomography images demonstrating infiltrative soft tissue with calcium deposits and consequent multifocal narrowing of the pulmonary arteries, veins, and bronchi.
Contributor Notes
Disclosure: ADB, none. LMG is a consultant and speaker for United Therapeutics, Janssen and Janssen, and Bayer Pharmaceuticals.